Extended Data Fig. 8: Clinical correlates of secretion and gamma-carboxylation scores map to FIX biochemical features.
From: Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP
a, Scatter plot of the mean and standard error of light chain secretion scores (n = 2 replicates) and FIX plasma antigen from individuals with hemophilia B in the EAHAD database (n = 416 variants). Light chain epitope-adjacent positions identified in Extended Data Fig. 4a are removed (n = 19 variants across 38 individuals)11. Dashed horizontal line is 40% FIX plasma antigen. Dashed vertical line is the 5th percentile of the synonymous secretion score distribution. b, Comparison of hemophilia B severity from individuals with hemophilia B in the EAHAD database (n = 1,781 variants) with light chain secretion scores. Light chain epitope-adjacent positions identified in Extended Data Fig. 4a are removed (n = 40 variants). Violin plot shows distribution of points with an inset box plot representing the 25th, 50th, and 75th percentiles. Whiskers span the range of data. Dashed horizontal line is the 5th percentile of the synonymous secretion score distribution. p values from a Kruskal–Wallis test adjusted for multiple comparisons by post-hoc Dunn’s test are shown. c, Scatter plot of the mean and standard error of light chain secretion scores (n = 2 replicates) and FIX plasma antigen from individuals harboring gain-of-cysteine variants in the EAHAD database (n = 9 variants across 27 individuals)11. Dashed horizontal line is 40% FIX plasma antigen. Dashed vertical line is the 5th percentile of the synonymous secretion score distribution. d, Bar plot of hemophilia B disease severity in the EAHAD database for individuals harboring gain-of-cysteine variants. e, Bar plot of the number of FIX variants in the EAHAD database and their classification using the random forest model trained on MultiSTEP functional data, by disease severity. Color indicates model prediction. f, Bar plot of the number of FIX propeptide and Gla domain variants in the EAHAD database and their classification using the random forest model trained on MultiSTEP functional data, by disease severity. Color indicates model prediction.
